This Program Project focuses on the role of biomechanical factors in modulating inflammation and cartilage matrix metabolism in osteoarthritis. The project brings together investigators from several departments in a multidisciplinary approach to investigate specific biomechanical, molecular, and psychological mechanisms that relate to disease outcome. A focal point of the program is the quantitative study of biomarkers of inflammation, pain, and matrix metabolism in three interrelated studies, performed at the in vivo (human and experimental animal) and in vitro levels. Project 1 will use a novel in vitro explant model to examine the role of specific biomechanical factors in modulating pro-inflammatory mediators and cytokines in cartilage and to also examine the influence of these factors on cartilage matrix metabolism and biomarker production. Project 2 investigates the interaction of biomechanical and inflammatory factors in a transgenic mouse model of OA that harbors a mutated sequence in the alpha-I (XI) gene encoding type XI collagen. Project 3 is a clinical study to develop more effective exercise and weight-loss therapies to reduce the pain, physical disability, and psychological distress experienced by overweight patients with persistent osteoarthritic knee pain. These projects are supported by two Core facilities. Core A (Administrative Core) will coordinate the administration and research activities of the three projects and to facilitate the research goals of the projects. Core B (Biomarker and Skeletal Phenotyping Core) will serve as a centralized facility for novel reagents, techniques, and training for quantitation of biological and immunohistochemical markers of cartilage metabolism in tissues and in fluids such as synovial fluid, serum, and tissue culture media. This strategy and the focused nature of the program allows a mechanistic investigation of the overall theme of the project in a manner that can readily be translated from basic science experiments to clinical therapies and outcomes. The information gained from this Program Project will provide important insights into the development new pharmacologic, psychological, and physical therapies for the treatment of osteoarthritis.